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Hypophosphatasia
This condition results from insufficient activity of an enzyme called tissue-nonspecific alkaline phosphatase. It affects people differently, with symptoms ranging from severe, life-threatening forms in infancy to milder forms appearing later in life, impacting bone strength and development.
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Overview
Hypophosphatasia is a rare inherited metabolic disorder that affects the development of bones and teeth. It is caused by genetic changes that lead to low levels of an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP) [PMID:30177727]. This enzyme is crucial for the process of mineralisation, where minerals like calcium and phosphate are deposited into the growing bones and teeth to make them hard and strong. When TNSALP activity is too low, bones and teeth do not mineralise properly, becoming soft and weak. This can lead to various skeletal problems, including rickets in children and osteomalacia in adults.
The condition can manifest with a wide spectrum of severity, from a severe, often life-threatening form in babies, to milder forms that may only appear in adulthood or even remain undiagnosed. The specific symptoms and their impact depend largely on the age at which the condition presents and the severity of the enzyme deficiency.
Symptoms & clinical features
The symptoms of hypophosphatasia vary significantly depending on the age of onset and the severity of the condition. In severe forms, particularly in infants, symptoms can include skeletal deformities, soft bones (rickets), respiratory problems due to soft rib cages, and poor feeding. Babies may have short limbs and a soft skull.
Children with less severe forms might experience bowed legs, delayed walking, premature loss of primary (milk) teeth, bone pain, and recurrent fractures. Adults may present with osteomalacia, which causes softening of the bones, chronic bone pain, frequent fractures, muscle weakness, and early loss of adult teeth. Dental problems, such as premature tooth loss, can be a key indicator at any age [PMID:30177727].
Some individuals with very mild forms of hypophosphatasia may have few or no obvious symptoms, with the condition only discovered incidentally or through a family history.
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Affected organs
Hypophosphatasia primarily affects the skeletal system and teeth. Bones throughout the body can be impacted, leading to softening, weakening, and impaired development. This can result in skeletal deformities, particularly in the limbs, skull, and rib cage.
Teeth are also significantly affected, with premature loss of both primary and adult teeth being a common feature. In severe cases, the respiratory system can be compromised due to poorly mineralised ribs, leading to breathing difficulties. Kidneys may also be affected, with some individuals developing nephrocalcinosis (calcium deposits in the kidneys) [PMID:30177727]. Muscle weakness can also be a feature, contributing to difficulties with mobility.
Risks & severity
The severity of hypophosphatasia is highly variable. The most severe form, known as perinatal or infantile hypophosphatasia, can be life-threatening due to severe skeletal abnormalities and respiratory complications. These forms typically present shortly after birth or in early infancy and can lead to a high mortality rate.
Milder forms, such as childhood hypophosphatasia, typically appear later in childhood and are associated with rickets, bone pain, and premature tooth loss. Adult hypophosphatasia often involves osteomalacia, chronic pain, and fractures, sometimes only becoming apparent in middle age. Odontohypophosphatasia, the mildest form, primarily affects the teeth, with early tooth loss being the main symptom and little to no skeletal involvement.
The exact prevalence of hypophosphatasia is estimated to be between 1 in 100,000 and 1 in 300,000 births, though milder forms may be underdiagnosed.
Genetic causes
Hypophosphatasia is caused by pathogenic variants in the ALPL gene. This gene provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP plays a vital role in bone mineralisation by breaking down certain molecules, such as pyrophosphate, which normally inhibit calcium and phosphate deposition in bones and teeth.
When there are pathogenic variants in the ALPL gene, the TNSALP enzyme either does not work correctly or is produced in insufficient amounts. This leads to an accumulation of pyrophosphate and other substances, which then prevent the proper mineralisation of bones and teeth. As a result, bones remain soft and pliable, leading to the characteristic features of hypophosphatasia.
- ALPL alkaline phosphatase, biomineralization associatedThe ALPL gene provides instructions for an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP), which is crucial for the proper development and mineralisation of bones and teeth.
Inheritance pattern
Hypophosphatasia is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered ALPL gene - one from each parent - to develop the condition. People who have only one copy of the altered gene are known as carriers. Carriers typically do not show symptoms of hypophosphatasia because their one working copy of the gene produces enough TNSALP enzyme for normal function.
When both parents are carriers of a pathogenic ALPL variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and be affected by hypophosphatasia. There is a 50% (2 in 4) chance that the child will be a carrier, and a 25% (1 in 4) chance that the child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of hypophosphatasia typically begins with clinical suspicion based on characteristic symptoms like skeletal abnormalities, bone pain, or premature tooth loss, combined with low levels of serum alkaline phosphatase (ALP) in blood tests. However, it's important to note that ALP levels are often low in infants and children, so careful interpretation is needed.
To confirm the diagnosis, genetic testing for pathogenic variants in the ALPL gene is usually performed. This testing can identify the specific genetic changes causing the condition and is available through the NHS Genomic Medicine Service (GMS) pathways. A referral to a clinical genetics service is often the route to accessing such testing (R-code R115, R116). Additionally, elevated levels of certain metabolites like pyridoxal-5'-phosphate (PLP) and phosphoethanolamine (PEA) in blood or urine can support a diagnosis [PMID:35711685].
Management & lifestyle
Management of hypophosphatasia is highly individualised and depends on the severity and symptoms experienced. For severe forms, enzyme replacement therapy is available to help improve bone mineralisation and overall health [PMID:35711685]. This therapy is a specialised treatment and would be managed by a team of experts within the NHS.
For milder forms, management often focuses on supportive care, which may include pain management, physiotherapy to maintain mobility and muscle strength, and orthopaedic interventions for skeletal deformities. Regular dental care is crucial due to the significant impact on teeth. Monitoring of bone health, kidney function, and overall development is also part of routine care. Genetic counselling is recommended for affected individuals and their families to understand the inheritance pattern and reproductive risks.
UK care pathway
In the UK, individuals suspected of having hypophosphatasia can be referred to a clinical genetics service or specialist metabolic centre. These services operate within the NHS Genomic Medicine Service (GMS) pathways. Clinical geneticists and genetic counsellors can provide diagnosis, information, and support, and facilitate access to appropriate genetic testing. Genetic testing for hypophosphatasia falls under specific R-codes (e.g., R115, R116) within the NHS GMS, allowing for comprehensive genomic analysis of the ALPL gene. This ensures that care is aligned with national standards and best practices.
Frequently asked questions
What is tissue-nonspecific alkaline phosphatase (TNSALP)?
TNSALP is an enzyme primarily found in bones, liver, and kidneys. It plays a critical role in mineralising bones and teeth by breaking down certain molecules that would otherwise prevent the deposition of calcium and phosphate, which are essential for strong bone formation.
Can hypophosphatasia be treated?
Yes, for severe forms of hypophosphatasia, enzyme replacement therapy is available and has shown to improve bone mineralisation and overall health. For milder forms, treatment focuses on managing symptoms, such as pain relief, physiotherapy, and dental care.
If I am a carrier, will I develop hypophosphatasia?
Typically, carriers of one altered ALPL gene copy do not develop symptoms of hypophosphatasia. They have enough functional TNSALP enzyme from their other normal gene copy to prevent the condition from manifesting. Carriers can pass the gene variant to their children.
How is hypophosphatasia diagnosed in the UK?
Diagnosis typically involves blood tests to check alkaline phosphatase levels, followed by genetic testing of the ALPL gene to confirm pathogenic variants. This testing is usually arranged through NHS clinical genetics services following a referral from a doctor.
Is dental care important for people with hypophosphatasia?
Yes, dental care is extremely important. Individuals with hypophosphatasia often experience premature loss of primary and adult teeth. Regular check-ups and appropriate dental interventions are crucial to manage these issues and maintain oral health.
References
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- Adam MP, Bick S, Mirzaa GM. Hypophosphatasia. 1993. PMID: 20301329
- Linglart A, Biosse-Duplan M. Hypophosphatasia. Current osteoporosis reports. 2016. PMID: 27084188
- Mornet E. Hypophosphatasia. Best practice & research. Clinical rheumatology. 2008. PMID: 18328985
- Mornet E. Hypophosphatasia. Orphanet journal of rare diseases. 2007. PMID: 17916236
- Briot K, Roux C. Adult hypophosphatasia. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie. 2017. PMID: 29405936
- Khan AA, Rush ET, Wakeford C. Key Learnings from Clinical Research and Real-World Evidence on Asfotase Alfa Effectiveness in Hypophosphatasia: 10 Years Post-Approval. Advances in therapy. 2025. PMID: 40715944
- Di Rocco F, Baujat G, Cormier-Daire V. Craniosynostosis and hypophosphatasia. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie. 2017. PMID: 29405940